A four-year study is proposed to investigate the effects of current persistent or previous habitual smoking of cocaine on the lung. The proposed study would expand on findings from our previous study of the pulmonary effects of regular smoking of cocaine with and without marijuana and/or tobacco. Specific attention will be paid to possible effects of habitual cocaine smoking on 1) respiratory symptoms and pulmonary physiology, 2) airway epithelial histopathology and alveolar cytology, and 3) pulmonary alveolar host defenses. Pulmonary physiologic effects of cocaine that will be investigated include alterations in ventilatory mechanics, airway reactivity, gas transfer (i.e., diffusing capacity, fractionated into its alveolar-capillary membrane and capillary blood volume components), exercise tolerance, gas exchange during maximum exercise, alveolar epithelial permeability (assessed by measurement of lung clearance of radiolabeled DTPA) and pulmonary and systemic vascular pressures and resistance. These physiologic studies will be carried out in selected cocaine smokers with an without demonstrable diffusion impairment, as well as before and immediately after experimental administration of cocaine (in smoked form or intravenously), to investigate the mechanism and clinical significance of the reduction in single-breath diffusing capacity previously observed by us and others in association with heavy cocaine smoking, even in the absence of marijuana and/or tobacco. To further investigate effects of cocaine smoking on bronchial epithelial histopathology and alveolar cell numbers, type and function, fiberoptic bronchoscopy, bronchial mucosal biopsies and bronchoalveolar lavage (BAL) will be performed in smokers of cocaine alone (n=24), cocaine and marijuana (n=24), cocaine and tobacco (n=24), marijuana only (n=24) and tobacco only (n=24) and 24 nonsmokers. Material obtained from BAL, including pulmonary alveolar macrophages (PAMs) and alveolar epithelial lining fluid (ELF) from these subjects will also be used to investigate the effect of cocaine smoking on pulmonary alveolar host defenses. Specifically, BAL-derived cells and fluid will be used to examine the effect of cocaine smoking on a) cytoskeletal-related functions of PAMs (chemotaxis to bacterial stimuli and complement; phagocytosis of opsonized and opsonized bacteria; O2- dependent and O2-independent mechanisms of bacterial killing and destruction; F-actin content and assembly in response to phagocytic stimuli); b) antibacterial activity of PAMs against S. aureus and E. coli; and c) pulmonary interstitial lymphocytes, epithelial cells and components of alveolar epithelial lining fluid that are important in the lung's defense against infection.